Control of excitatory synaptic transmission by C-terminal Src kinase

J Biol Chem. 2008 Jun 20;283(25):17503-14. doi: 10.1074/jbc.M800917200. Epub 2008 Apr 29.

Abstract

The induction of long-term potentiation at CA3-CA1 synapses is caused by an N-methyl-d-aspartate (NMDA) receptordependent accumulation of intracellular Ca(2+), followed by Src family kinase activation and a positive feedback enhancement of NMDA receptors (NMDARs). Nevertheless, the amplitude of baseline transmission remains remarkably constant even though low frequency stimulation is also associated with an NMDAR-dependent influx of Ca(2+) into dendritic spines. We show here that an interaction between C-terminal Src kinase (Csk) and NMDARs controls the Src-dependent regulation of NMDAR activity. Csk associates with the NMDAR signaling complex in the adult brain, inhibiting the Src-dependent potentiation of NMDARs in CA1 neurons and attenuating the Src-dependent induction of long-term potentiation. Csk associates directly with Src-phosphorylated NR2 subunits in vitro. An inhibitory antibody for Csk disrupts this physical association, potentiates NMDAR mediated excitatory postsynaptic currents, and induces long-term potentiation at CA3-CA1 synapses. Thus, Csk serves to maintain the constancy of baseline excitatory synaptic transmission by inhibiting Src kinase-dependent synaptic plasticity in the hippocampus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • COS Cells
  • CSK Tyrosine-Protein Kinase
  • Chlorocebus aethiops
  • Dendrites / metabolism
  • Hippocampus / metabolism
  • Humans
  • Long-Term Potentiation
  • Models, Biological
  • Neurons / metabolism*
  • Protein-Tyrosine Kinases / metabolism*
  • Signal Transduction
  • Subcellular Fractions
  • Synaptic Transmission*
  • src-Family Kinases / metabolism*

Substances

  • Protein-Tyrosine Kinases
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • CSK protein, human